Foldamers: Novel Ligands for Diverse Protein Surfaces

描述(申请人提供)：本申请建立在我们实验室最新结果的基础上，详细介绍了设计在水中高度14-螺旋并与蛋白质表面高度亲和力结合的β-多肽的一般策略，例如Hdm2的p53AD相互作用结构域。在目标1中，我们探索了有助于14-螺旋在水中稳定的结构特征以及14-螺旋β-肽Beta53-1识别蛋白质表面的能力。我们将完成广泛的“主客体”分析，将所有蛋白质产生的和选定的非蛋白质产生的侧链归类为14-螺旋稳定、不稳定或中性，产生一个与位置相关的水中14-螺旋倾向性的数据库；确定Beta53-1的核磁共振溶液结构以支持主客数据并指导未来的设计工作；并探索是否可以通过引入环状ACHC残基来改善Beta53-1的稳定性或亲和力。在目标2中，我们以目标1的结果为基础，为威胁人类健康、国家安全或两者兼而有之的3种病毒的包膜糖蛋白设计β-肽配体：HIV、人类呼吸道合胞病毒(HRSV)和引起严重急性呼吸综合征(SARS-CoV)的冠状病毒。Aim 2中的实验将在一个高度相关和易处理的系统中验证我们的倍他肽设计策略，并可能为未来的药物开发提供线索。在目标3中，我们开发了合成、分析和筛选β-肽组合文库的方法，并使用它们来优化目标1和目标2中确定的β-肽的亲和力(并最小化其大小)。这一目标还包括一项识别细胞渗透性β53-1文库成员的实验，这些信息将指导针对其他有效靶点的β-肽配体的设计。综上所述，这一应用中的实验将提供关于配体设计的基本信息，并有助于实现化学生物学研究中最核心和关键(尚未实现)的目标之一，即为大量潜在的非酶蛋白质靶标快速鉴定高亲和力配体。

DESCRIPTION (provided by applicant): This application builds on a foundation of recent results from our laboratory detailing a general strategy for the design of beta-peptides that are highly 14-helical in water and bind with high affinity to protein surfaces, such as the p53AD interaction domain of hDM2. In Aim 1 we explore the structural features that contribute to 14-helix stability in water and the ability of the 14-helical beta-peptide beta53-1 to recognize protein surfaces. We will complete an extensive "host-guest" analysis that will classify all proteinogenic and selected non-proteinogenic side chains as 14-helix stabilizing, destabilizing, or neutral, generating a database of position-dependent, 14-helix propensities in water; determine the NMR solution structure of beta53-1 to support the host-guest data and guide future design efforts; and explore whether the stability or affinity of beta53-1 can be improved by introduction of cyclic ACHC residues. In Aim 2 we build on the results of Aim 1 to design beta-peptide ligands for the envelope glycoproteins of 3 viruses that threaten human health, national security, or both: HIV, human respiratory syncytial virus (HRSV), and the coronavirus that causes severe acute respiratory syndrome (SARS-CoV). The experiments in Aim 2 will validate our betapeptide design strategy in a system that is highly relevant and tractable, and will likely provide leads for future drug development. In Aim 3 we develop methods to synthesize, analyze, and screen beta-peptide combinatorial libraries, and use them to optimize the affinities (and minimize the size) of beta-peptides identified in Aims 1 and 2. This aim also includes an experiment to identify cell-permeable beta53-1 library members, information that will guide design of beta-peptide ligands for additional validated targets. Taken together, the experiments in this application will provide fundamental information on ligand design and help achieve 1 of the most central and critical (yet unmet) goals of chemical biology research, the rapid identification of high affinity ligands for the vast array of potential non-enzymatic protein targets.